From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.
From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations.
复制标题
从CFTR生物学到联合药物疗法：囊性纤维化突变的分类扩大。
DOI：
10.1091/mbc.e14-04-0935
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发表时间：
2016-02-01
影响因子：
3.3
通讯作者：
Lukacs GL
中科院分区：
文献类型：
--
作者：
Veit G;Avramescu RG;Chiang AN;Houck SA;Cai Z;Peters KW;Hong JS;Pollard HB;Guggino WB;Balch WE;Skach WR;Cutting GR;Frizzell RA;Sheppard DN;Cyr DM;Sorscher EJ;Brodsky JL;Lukacs GL
囊性纤维化跨膜传导调节因子(CFTR)的2000多个突变已被描述，它们赋予了一系列分子细胞生物学和功能表型。这些突变中的大多数会导致分泌上皮细胞顶端质膜的负离子电导受损，并导致不同疾病严重程度的囊性纤维化(CF)。基于cftr突变体的分子表型复杂性及其对药物治疗的敏感性，人们已经认识到突变可能在cftr通道生物学中造成组合缺陷。这一概念导致了这样的结论：针对单一缺陷(如转录、翻译、折叠和/或门控)的药物治疗组合可能比现有的低效单一治疗显示出更好的临床益处。事实上，最近的3期临床试验结合了iVacaftor(一种门控增强剂)和Lumacaftor(一种折叠校正器)，已经证明对携带最常见突变(残基F508、ΔF508或Phe508del缺失)的CF患者有效。这种药物组合最近被美国食品和药物管理局批准用于ΔF508纯合子患者。对罕见突变引起的结构、细胞生物学和功能缺陷的最新研究提供了一个新的框架，揭示了不同CFTR等位基因的混合缺陷。建立一套先前定义的CF等位基因基本缺陷的组合类别将有助于为CF患者设计更有效的治疗措施。
More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.